Fibrin sealant is typically a blood product obtained from either commercial sources or some regional blood transfusion centers. Components that are commonly used in the preparation of fibrin sealants are predominantly fibrinogen supplemented with various quantities of Factor VIII, Factor XIII, fibronectin, vitronectin and von Willebrand factor (vWF). The fibrinogen component is typically activated by the last protease of the coagulation cascade-thrombin.
Fibrin sealant is formed by an enzymatic reaction involving inter alia, fibrinogen, thrombin and Factor XIII. The thrombin converts the fibrinogen to fibrin by enzymatic action at a rate determined by the concentration of thrombin. Factor XIII, is typically present in the fibrinogen component of the sealant and is an enzyme of the blood coagulation system that cross-links and stabilizes the fibrin clot. This process bypasses most of the steps of normal coagulation and mimics its last phase. Some manufacturers add anti-proteolytic agents to the fibrin sealant formulation (as described in WO 93/05822) or specifically remove the plasminogen in order to stop or delay the fibrinolysis (as described in U.S. Pat. No. 5,792,835 and U.S. Pat. No. 7,125,569).
U.S. Pat. No. 4,427,650 discloses a tissue adhesive which can be applied in the form of dry, powdery mixture immediately and directly onto the wound or in the area of operation. The adhesive consists of solid, powdery, biologically active constituents and contains 60 to 96% by weight of fibrinogen, which is largely liberated from cryo-insoluble globulin, 0.05 to 5% by weight of fibrinolysis inhibitor, and 0.1 to 15% by weight of thrombin and/or prothrombin.
U.S. Pat. No. 5,962,405 discloses a lyophilized fibrinogen preparation for preparing a fibrinogen solution for use as a tissue adhesive. The fibrinogen preparation contains a solubility improving substance.
It has been known for some time that fibrin sealant may be applied to wounds, such as open wounds of a person, to close the wound, stop the bleeding, and prevent other substances, such as infectious agents, from entering the wound.
The effect of fibrin sealant in sealing defects in tissues which are under constant movement, e.g. gastrointestinal tissue and lung tissue, has been reported. However, there is discrepancy in these reports.
One reported approach to diminish post-operative defects such as leaks at the staple or suture (staple/suture) line after gastrointestinal resection is to use staple/suture line reinforcements. Different staple/suture line reinforcement products are commercially available. For example, physicians have tried non- or semi absorbable staple line reinforcement products such as Seamguard®, Peristrips Dry®, and Surgisis®. However, in early experimental and clinical studies, absorbable staple line reinforcement material appears to have considerable advantages over non- or semi absorbable staple line reinforcement material (Yo et al. “Buttressing of the staple line in gastrointestinal anastomoses: overview of new technology designed to reduce perioperative complications”. Dig Surg. 2006; 23:283-291). Recent reports using fibrin as absorbable staple line reinforcement for the prevention of gastrointestinal post-operation leaks (Fullum et al. “Decreasing anastomotic and staple line leaks after laparoscopic Roux-en-Y gastric bypass”. Surg Endosc. 2009; 23:1403-1408; Efthimiou et al. “Fibrin sealant associated with increased body temperature and leukocytosis after laparoscopic gastric bypass”. Surg Obes Relat Dis. 2009 Mar. 17) suggest that the current fibrin sealant formulations are not adequate for staple/suture line reinforcement.
U.S. Pat. No. 5,690,675 discloses closing wounds in lung tissue by a two step method consisting essentially of applying fasteners (e.g. staples, clips, pins, hooks) to a region adjacent to the wound, wherein the fasteners may cause penetrations. The fasteners are present in a preformed layer of collagen, fibrin, fibrinogen, elastin, albumin, or a combination thereof, and energy is applied to the region to fuse the material to the tissue and seal perforations in the tissue.
U.S. Pat. No. 5,883,078 discloses a stable tissue adhesive which comprises fibrinogen and an activator or pro-activator of prothrombin. The adhesive can be present as a liquid or dry preparation. In one embodiment, a solid, 2-sided adhering tissue adhesive is made by applying the dry adhesive in solid form to a wound surface and the second wound surface (the second tissue part) is subsequently adapted and shortly pressed together. The preparation promptly dissolves by means of the blood and/or wound secretion present and subsequently solidifies with the commencement of coagulation, whereby the adhering and hemostatic effect is achieved. The solid, 2-sided adhering tissue adhesive is especially suitable for joining soft tissue parts such as liver or spleen.
Lillemoe et al. [(2004) J Gastrointest Surg., Vol. 8, No. 7 pp 766-774 A journal article entitled “Does Fibrin Glue Sealant Decrease the Rate of Pancreatic Fistula After Pancreaticoduodenectomy? Results of a Prospective Randomized Trial] showed that topical application of fibrin glue sealant to the surface of the pancreatic anastomosis did not reduce the incidence of pancreatic fistula or total complications in patients after pancreaticodudodenectomy and concludes that there seems to be no benefit regarding the use of this substance in this setting.
Another study (“The sealing effect of fibrin glue against alveolar air leakage evaluated up to 48 h; comparison between different methods of application” Kawamura et al. (2005) Eur J of Cardiothorac Surg. 28(1):39-42) discloses the sealing effect of fibrin glue against alveolar air leakage in an animal model and evaluates different methods of application. Solution A consisting of a protein concentrate comprising fibrinogen and a solution B comprising thrombin were used. In the rubbing and spray method, solution A was dripped and gently rubbed onto the air leakage area. Then both solutions were sprayed simultaneously as a mixed aerosol. In another method, a double layer was prepared by dripping solution A onto the air leakage surface after which solution B was dripped. In another method, a collagen fleece coated with dry fibrinogen and thrombin on one side (TachoComb) was used in animal (dog) models and checked after 24 hours. According to the authors, the sealing effect of fibrin glue is relatively unstable up to 12 hours after its application. Also, the authors concluded that the rubbing and spray method may help the fibrin seal to reach its full strength faster compared with the other two methods.
Another study by Yo et al (2006) (Dig Surg 23: 283-291) discloses efforts to reduce anastomotic complications like bleeding or leakage at the staple line when performing gastrointestinal resections. Yo indicated that in animal models of rat colonic anastomosis, the application of fibrin glue to seal and prevent leakage appears not to be a feasible technique. It is disclosed that in gastric resection, the application of fibrin glue to support and seal off the staple line seemed more successful.
U.S. Pat. No. 7,196,054 discloses a method for treating wounded tissue in a patient, comprising applying to the wounded tissue a composition in the form of a dry powder comprising fibrinogen in an amount which forms a fibrin matrix in the presence of thrombin, Factor XIII, Ca2+, and aqueous solution; providing to the composition, thrombin, Factor XIII, Ca2+ and aqueous solution in amounts which form a fibrin matrix in the presence of fibrinogen.
Fullum et al. (2009) discloses that anastomotic and staple line leaks (ASL) occur after laparoscopic Roux-en-Y gastric bypass (LRYGB) in obese patients. Fibrin sealant was placed along the gastric staple line. The authors concluded that the operative technique, including the proper staple size, staple line reinforcement, handsewn otomy closure, stay sutures, intraoperative leak testing, and fibrin sealants, was instrumental in decreasing the incidence of ASL after LRYGB. The authors were unable to determine if any one component was most crucial in preventing ASL.
In contrast, Efthimiou et al. 2009 discloses that fibrin sealant use had no effect on the anastomotic or staple line leak rate in LRYGB.
There is an unmet need for a superior fibrin sealant formulation for sealing defects in tissues that are in constant movement e.g. gastrointestinal tissue and lung tissue.